Identification of two novel RRM2B variants associated with autosomal recessive progressive external ophthalmoplegia in a family with pseudodominant inheritance pattern

• Published in: Journal of human genetics 2023-08, Vol.68 (8), p.527-532
• Main Authors: Restrepo-Vera, Juan Luis, Rovira-Moreno, Eulàlia, Ramón, Javier, Codina-Sola, Marta, Llauradó, Arnau, Salvadó, Maria, Sánchez-Tejerina, Daniel, Sotoca, Javier, Martínez-Sáez, Elena, Martí, Ramon, García-Arumí, Elena, Juntas-Morales, Raul
• Format: Article
• Language: English
• Subjects: Adult; Age; Biopsy; Cell culture; Cell Cycle Proteins - genetics; Child; Cytochrome-c oxidase; DNA biosynthesis; DNA, Mitochondrial - genetics; Fibroblasts; Humans; Inheritance Patterns; Mitochondrial DNA; Next-generation sequencing; Ophthalmoplegia; Ophthalmoplegia, Chronic Progressive External - genetics; Ophthalmoplegia, Chronic Progressive External - pathology; p53 Protein; Pathogenicity; Ribonucleotide Reductases - genetics; Skeletal muscle
• ISSN: 1434-5161; 1435-232X
• DOI: 10.1038/s10038-023-01144-2

RRM2B encodes the p53-inducible small subunit (p53R2) of ribonucleotide reductase, a key protein for mitochondrial DNA (mtDNA) synthesis. Pathogenic variants in this gene result in familial mitochondrial disease in adults and children, secondary to a maintenance disorder of mtDNA. This study describes two patients, mother and son, with early-onset chronic progressive external ophthalmoplegia (PEO). Skeletal muscle biopsy from the latter was examined: cytochrome c oxidase (COX)-negative fibres were shown, and molecular studies revealed multiple mtDNA deletions. A next-generation sequencing gene panel for nuclear-encoded mitochondrial maintenance genes identified two unreported heterozygous missense variants (c.514 G > A and c.682 G > A) in the clinically affected son. The clinically affected mother harboured the first variant in homozygous state, and the clinically unaffected father harboured the remaining variant in heterozygous state. In silico analyses predicted both variants as deleterious. Cell culture studies revealed that patients' skin fibroblasts, but not fibroblasts from healthy controls, responded to nucleoside supplementation with enhanced mtDNA repopulation, thus suggesting an in vitro functional difference in patients' cells. Our results support the pathogenicity of two novel RRM2B variants found in two patients with autosomal recessive PEO with multiple mtDNA deletions inherited with a pseudodominant pattern.